Seliciclib (roscovitine or CYC202) is an experimental

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

candidate in the family of pharmacological

cyclin-dependent kinase Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They a ...

(CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2,

CDK7 Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the ''CDK7'' gene. The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are h ...

and CDK9, which alter the growth phase or state within the

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...

of treated

cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

. Seliciclib is being developed by

Cyclacel {{Infobox company , , name = Cyclacel Pharmaceuticals, Inc. , logo = Cyclacel.png , type = Public , traded_as = {{NASDAQ, CYCC , foundation = 1997 , location = Berkeley Heights, New Jersey, U.S. , key_people = Spiro Rombotis, CEO David P. ...

.This is a phase II, dose ranging, multicenter, randomized, double-blind, placebo-controlled study. The aim of this study is to assess the safety of increasing doses of roscovitine administered orally for 4 cycles of 4 consecutive days (treatment "on") separated by a 3 days treatment free period (treatment "off") in adult CF subjects with Cystic Fibrosis carrying 2 Cystic Fibrosis causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa. This study involved 36 Cystic Fibrosis patients: 24 treated and 12 controls. Seliciclib is being researched for the treatment of non-small cell lung cancer (NSCLC), Cushing's disease,

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

, HIV infection, Parkinson’s disease, herpes simplex infection,

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

,3-byrazines derivatives as submicromolar affinity activators of wild type, G551D, and F508del cystic fibrosis transmembrane conductance regulator chloride channels.J Pharmacol Exp Ther. 2006 Oct;319(1):349-59.Noel S, Faveau C, Norez C, Rogier C, Mettey Y, Becq F."> and the mechanisms of chronic

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

disorders. Seliciclib is a 2,6,9-substituted

purine Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...

analog. Its structure in complex with CDK2 was determined in 1996. Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.

Clinical trials and lab tests

Cancer treatment

Seliciclib has been found to produce

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

in treated cancerous cells of non-small cell lung cancer (NSCLC) and other cancers. Seliciclib has previously undergone Phase IIa clinical trials, in 240 NSCLC patients as a combined dose with existing first- and second-line treatments. In the current ''APPRAISE'' trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients. The

side-effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

reported in Phase I trials of seliciclib for NSCLC were "

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, vomiting, transient elevations in serum creatinine and liver function parameters and transient hypokalemia".

Immunological disorders

Seliciclib is also in clinical trials for

B-cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...

lymphomas, including

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...

. Seliciclib has been shown to inhibit

RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryoti ...

-dependent

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

and down-regulation of the protein MCL1. Seliciclib has been shown ''in vitro'' to induce

neutrophil granulocytes Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

. If this mechanism turns out to be safe, reliable and efficient ''in vivo'', the drug could improve treatment of chronic inflammation diseases such as

and

arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...

. These are usually treated with

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

s which often have serious side effects

Neurological therapies

In the nervous system, seliciclib has been shown to suppress

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...

l activation and to provide some neuroprotection in animal models of cerebral ischemia. Furthermore, it increases antitumor activity of

temozolomide Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. Text was copied from this source which is © European Medicines Agency. Reproduction i ...

in treatment of glioblastoma multiforme and is considered as a possible therapeutic option for glioma.

Antiviral effect

Seliciclib is also a possible antiviral agent. It causes the death of cells infected with

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

and preventing the replication of herpes simplex virus.

Ovum production

Seliciclib has been shown to cause parthogenetic egg activation. However it does create abnormal second polar bodies and therefore possible aneuploid zygotes. Egg activation usually involves calcium oscillations however this does not happen with seliciclib. Seciclib causes egg activation by inhibiting protein kinases which results in the inactivation of the maturation promoting factor (MPF).

Renal hypertrophy

Seliciclib reduces renal hypertrophy by 45% after 5/6 nephrectomy.

Side effects

Causes sever side effect that can not be tolerated on daily bases. Side effects include hypokalemia and elevation of liver enzymes. Due to these side effects Seliciclib has not been approved by the USFDA.

References

{{Intracellular chemotherapeutic agents Primary alcohols Purines Protein kinase inhibitors Experimental drugs Isopropyl compounds